The University of Tennessee, Memphis Hepatitis C Cooperative Research Center will use studies of HCV/host interactions to determine why African American patients with HCV respond poorly to standard therapy (interferon and ribavirin). Hepatitis C is common, 1.8% of all Americans, but is even more common among African Americans, and in persons living in poverty. In Memphis, 55% of the population is African American, 34% of whom live below the poverty line. In a previous study, we documented a response rate of only 5% in this population, contrasted with 40% in whites. We propose to systematically characterize the differences between African Americans and whites by allelic variations in cellular ligands/receptors for HCV (Project 1). In Project 2, we will continue to develop an in vitro system for studying HCV, a chimeric VSV virus with the hepatitis C E1 and E2 envelope proteins expressed on its surface. We will use this model to characterize virus/cell interactions, testing antibodies to specific dominant quasispecies, contrasting our African American patients with whites. We will further characterize the putative receptor for HCV, CD81, to define its associated proteins, possible co-receptors (Project 3). These data will interface back to our patients as we search for allelic variations between African Americans and whites to explain the differences in response to therapy. Using the surrogate virus model, we will also screen libraries of small molecules to search for compounds that can block E2/CD81 binding (Project # African American population responds so poorly. Understanding this phenomenon will provide insights into why present day therapy is still only moderately successful in all populations, will allow us to predict who is more likely to respond, and will pave the way to developing better therapy for this emerging health problem.